Therapeutic agent for chronic obstructive pulmonary disease and method for treating chronic obstructive pulmonary disease using the same

ABSTRACT

This therapeutic agent for chronic obstructive pulmonary disease comprises, an active ingredient, at least one of a 7-aminoquinolinone derivative represented by the general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a hydrogen atom or an alkyl group; R 2  and R 3  each represents a group selected from a hydrogen atom, an acyl group, an alkyl group and an alkenyl group; and R 4  and R 5  each represents a group selected from a hydrogen atom, an acyl group, an alkyl group, an alkenyl group and an aralkyl group, and its physiologically acceptable salt.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for chronicobstructive pulmonary disease comprising, as an active ingredient, a7-aminoquinolinone derivative and its physiologically acceptable salt,which is useful for treating chronic obstructive pulmonary disease, anda method for treating chronic obstructive pulmonary disease using thesame.

BACKGROUND ART

With respect to a quinolinone derivative, general quinolinonederivatives such as 3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone and8-methoxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone have hithertobeen known (see, for example, Non-Patent Document 1: “Journal ofHeterocyclic Chemistry 22, pages 1087-1088, 1985 (J. Heterocyclic Chem.,22, 1985)”). However, such a document does not describe that thesecompounds are useful as a specific therapeutic agent.

Also there have been known quinolinone derivatives which have oxygensdirectly bonded to carbons at the 3- and 4-positions and also have anamino group at the 7-position (see, for example, Patent Document 1:specification of U.S. Pat. No. 5,942,521 and Patent Document 2:specification of U.S. Pat. No. 6,136,822). In these documents, althoughan antiallergic action and an asthma treating action of a quinolinonederivative having an amino group have been studied, a therapeutic actionagainst specific symptoms of chronic obstructive pulmonary diseasethrough no antigen-antibody reaction has never been studied and also ithas never been known that such a quinolinone derivative is effective asa therapeutic agent for chronic obstructive pulmonary disease.

An object to be achieved by the present invention is to provide atherapeutic agent for chronic obstructive pulmonary disease, which hashigh safety and is effective on chronic obstructive pulmonary diseaseand also exhibits extremely excellent drug potency, and a method fortreating chronic obstructive pulmonary disease using the same.

DISCLOSURE OF THE INVENTION

To achieve the above object, the present inventors have synthesizedvarious compounds and evaluated drug potency and safety thereof. As aresult, they have found that a specific aminoquinolinone derivative isextremely excellent as a therapeutic agent for chronic obstructivepulmonary disease, and thus the present invention has been completed.

That is, the present invention is directed to a therapeutic agent forchronic obstructive pulmonary disease comprising, as an activeingredient, at least one of a 7-aminoquinolinone derivative representedby the general formula (I):

wherein R₁ represents a hydrogen atom or an alkyl group; R₂ and R₃ eachrepresents a group selected from a hydrogen atom, an acyl group, analkyl group and an alkenyl group; and R₄ and R₅ each represents a groupselected from a hydrogen atom, an acyl group, an alkyl group, an alkenylgroup and an aralkyl group, and its physiologically acceptable salt.

That is, the present invention is directed to use of at least one of the7-aminoquinolinone derivative and its physiologically acceptable saltfor treating chronic obstructive pulmonary disease.

Also, the present invention is directed to a therapeutic agent forchronic obstructive pulmonary disease comprising, as an activeingredient, the 7-aminoquinolinone derivative of the above generalformula (1) and its physiologically acceptable salt, wherein the chronicobstructive pulmonary disease is chronic bronchitis or pulmonaryemphysema. That is, the present invention is directed to use of at leastone of the 7-aminoquinolinone derivative and its physiologicallyacceptable salt for treating chronic bronchitis and pulmonary emphysema.

Furthermore, the present invention is directed to a method for treatingchronic obstructive pulmonary disease, which comprises using the7-aminoquinolinone derivative and its physiologically acceptable salt.

The present invention can provide a therapeutic agent for chronicobstructive pulmonary disease, which has high safety and also exhibitsextremely excellent drug potency to chronic obstructive pulmonarydisease, by using at least one of a specific 7-aminoquinolinonederivative and its physiologically acceptable salt as an activeingredient. That is, in the present invention, at least one of the7-aminoquinolinone derivative and its physiologically acceptable salt iseffective for treating chronic obstructive pulmonary disease.

BEST MODE FOR CARRYING OUT THE INVENTION

R₁ in the 7-aminoquinolinone derivative represented by the generalformula (I):

of the present invention is a hydrogen atom or an alkyl group. The alkylgroup in R₁ may be a linear or branched alkyl group.

Specific examples of the alkyl group include methyl group, ethyl group,propyl group, isopropyl group, n-butyl group, s-butyl group, n-pentylgroup, hexyl group, octyl group and decyl group, and the alkyl group ispreferably an alkyl group having 1 to 10 carbon atoms, and morepreferably 1 to 8 carbon atoms.

R₂ and R₃ of the general formula (I) are a hydrogen atom, an acyl group,an alkyl group or an alkenyl group. Examples of the acyl group includealkanoyl group such as formyl group, acetyl group, propionyl group orbutyryl group, and benzoyl group. The benzoyl group may have asubstituent and examples thereof include p-hydroxybenzoyl group,p-methoxybenzoyl group, 2,4-dihydroxybenzoyl group and2,4-dimethoxybenzoyl group. An alkanoyl group is preferable and anacetyl group is particularly preferable.

The alkyl group as for R₂ and R₃ may be a linear or branched alkylgroup, and examples thereof include methyl group, ethyl group, propylgroup, isopropyl group, n-butyl group, s-butyl group, n-pentyl group,hexyl group, octyl group and decyl group, and the alkyl group ispreferably an alkyl group having 1 to 10 carbon atoms, and morepreferably an alkyl group having 1 to 8 carbon atoms.

The alkenyl group as for R₂ and R₃ may be a linear or branched alkenylgroup, and examples thereof include vinyl group, propenyl group, hexenylgroup, octenyl group, prenyl group and geranyl group, and the alkenylgroup is preferably an alkenyl group having 2 to 10 carbon atoms.

In the general formula (I), R₄ and R₅ may be the same or different andrepresent a hydrogen atom, an acyl group, an alkyl group, an alkenylgroup or an aralkyl group. Examples of the acyl group include alkanoylgroup such as formyl group, acetyl group, propionyl group or butyrylgroup, benzoyl group, substituted benzoyl group, or cynnamoyl groupwhich may be substituted.

Examples of the substituted benzoyl group include p-hydroxybenzoylgroup, p-methoxybenzoyl group, 2,4-dihydroxybenzoyl group and2,4-dimethoxybenzoyl group. Examples of the cinnamoyl group which may besubstituted include cinnamoyl group, 2-hydroxycinnamoyl group,3-hydroxycinnamoyl group, 4-hydroxycinnamoyl group,3,4-dihydroxycinnamoyl group, 4-hydroxy-3-methoxycinnamoyl group,3-hydroxy-4-methoxycinnamoyl group and 3,5-dimethoxy-4-hydroxycinnamoylgroup. The cinnamoyl group is preferably cinnamoyl group which may besubstituted.

The alkyl group as for R₄ and R₅ of the general formula (I) may be alinear or branched alkyl group, and examples thereof include methylgroup, ethyl group, propyl group, isopropyl group, n-butyl group,s-butyl group, n-pentyl group, hexyl group, octyl group and decyl group.The alkyl group is preferably an alkyl group having 1 to 10 carbonatoms, and more preferably 1 to 8 carbon atoms.

The alkenyl group as for R₄ and R₅ may be a linear or branched alkenylgroup, and examples thereof include vinyl group, propenyl group, hexenylgroup, octenyl group, prenyl group and geranyl group. The alkenyl groupis preferably an alkenyl group having 2 to 10 carbon atoms.

Examples of the aralkyl group as for R₄ and R₅ include aralkyl groupssuch as benzyl group and substituted benzyl group (for example,p-methoxybenzyl group or p-hydroxybenzyl group). The present inventionalso includes a 7-aminoquinolinone derivative in which substituents asfor R₄ and R₅ of the 7-aminoquinolinone derivative represented by thegeneral formula (I) are the same substituents, and a 7-aminoquinolinonederivative in which different substituents selected from the above groupare combined.

The 7-aminoquinolinone derivative as the active ingredient of thetherapeutic agent for chronic obstructive pulmonary disease of thepresent invention can be prepared by appropriately selecting apreferable method according to the objective 7-aminoquinolinonederivative. For example, it can be prepared by the method described inJapanese Patent No. 2,943,725 or U.S. Pat. No. 6,136,822.

As an example, the method described in U.S. Pat. No. 6,136,822 will nowbe described.

By reacting an amide derivative represented by the general formula (II):

with a basic substance, an intramolecular cyclization reaction iscarried out as shown in the following scheme:

wherein R₆ represents a hydrogen atom, an alkyl group, an alkyl grouphaving a hydroxyl group, an alkenyl group or an aryl group; R₇represents an alkyl group, an alkenyl group, an aryl group or an aralkylgroup; R₈ represents a reactive carboxyl group; R₉, R₁₀ and R₁₂represent a hydrogen atom; and R₁₁ represents R₁₃R₁₄N— (wherein R₁₃ andR₁₄ each independently represents a hydrogen atom, an alkyl group, analkenyl group, an aralkyl group or an acyl group).

Examples of the basic substance include various compounds such as alkalimetal, alkali metal alkoxide, alkali earth metal alkoxide, alkali metalhydride, alkali earth metal hydride and alkali metal amide.

Examples of the alkali metal include alkali metals such as sodium andpotassium, examples of the alkali metal alkoxide include basicsubstances such as sodium methoxide, sodium ethoxide, sodium t-butoxideand potassium t-butoxide, and examples of the alkali earth metalalkoxide include magnesium methoxide, magnesium ethoxide, magnesiumt-butoxide, calcium methoxide, calcium ethoxide, calcium t-butoxide,barium methoxide, barium ethoxide and barium t-butoxide.

Examples of the alkali metal hydride include alkali metal hydrides suchas lithium hydride, sodium hydride and potassium hydride, and examplesof the alkali earth metal hydride include alkali earth metal hydridessuch as calcium hydride. Examples of the alkali metal amide includelithium amide, sodium amide, potassium amide, lithium diisopropylamide,lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide andpotassium bis(trimethylsilyl)amide.

The amount of the basic substance required for the cyclization reactionis usually from 1 to 5 mols, and preferably from 2 to 3 mols, per mol ofthe amide derivative to be reacted. When sodium hydride, potassiumt-butoxide or lithium diisopropylamide is used as the basic substance,enough amount is usually 2 mols per mol of the amide derivative.

The reaction in the method for preparing the 7-aminoquinolinonederivative is carried out in an organic solvent which does not inhibitthe reaction. Examples of the organic solvent include hydrocarbon-basedsolvents such as benzene and toluene; alcohol-based solvents such asmethanol, ethanol, propanol, isopropanol and t-butanol; ether-basedsolvents such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane;and amide-based solvents such as N,N-dimethylformamide and1-methyl-2-pyrolidinone.

Preferable organic solvent varies according to the kind of the basicsubstance to be used. For example, in case of the alkali metal alkoxide,an alcohol-based solvent is preferable. When the alkali metal amide suchas lithium amide, sodium amide or potassium amide is used, ammonia canbe used as the solvent.

The reaction temperature varies according to the kind of the basicsubstance and reaction solvent to be used, but is usually from −80° C.to 100° C., and preferably from −50° C. to 50° C., and the reaction timeis usually from 1 to 5 hours.

Specific examples of the thus obtained 7-aminoquinolinone derivativerepresented by the general formula (I) of the present invention includecompounds represented by the following Tables 1 to 17.

TABLE 1 Compound No. R₁ R₂ R₃ R₄ R₅ 1 H Acetyl Methyl H H 2 H AcetylButyl H H 3 H Acetyl Hexyl H H 4 H Acetyl 3-Methyl- H H 2-butenyl 5 HAcetyl Geranyl H H 6 H Acetyl H H H 7 H Formyl Methyl H H 8 H FormylButyl H H 9 H Formyl Hexyl H H 10 H Formyl 3-Methyl- H H 2-butenyl 11 HFormyl Geranyl H H 12 H Formyl H H H 13 H Methyl Methyl H H 14 H MethylButyl H H 15 H Methyl Hexyl H H 16 H Methyl 3-Methyl- H H 2-butenyl 17 HMethyl Geranyl H H 18 H Methyl H H H 19 H Isopropyl H H H 20 H Butyl H HH 21 H Hexyl H H H 22 H 2-Methyl-pentyl H H H 23 H Octyl H H H 24 H2-Propenyl H H H 25 H Geranyl H H H 26 H H H H H 27 H H Methyl H H 28 HH Butyl H H 29 H H Hexyl H H 30 H H 3-Methyl- H H 2-butenyl 31 H HGeranyl H H 32 Methyl Acetyl Methyl H H 33 Methyl Acetyl Ethyl H H 34Methyl Acetyl Butyl H H 35 Methyl Acetyl Hexyl H H 36 Methyl Acetyl3-Methyl- H H 2-butenyl 37 Methyl Acetyl Geranyl H H 38 Methyl Acetyl HH H 39 Methyl Formyl Methyl H H 40 Methyl Formyl Butyl H H

TABLE 2 Compound No. R₁ R₂ R₃ R₄ R₅ 41 Methyl Formyl Hexyl H H 42 MethylFormyl 3-Methyl- H H 2-butenyl 43 Methyl Formyl Geranyl H H 44 MethylFormyl H H H 45 Methyl Methyl Methyl H H 46 Methyl Methyl Butyl H H 47Methyl Methyl Hexyl H H 48 Methyl Methyl 3-Methyl- H H 2-butenyl 49Methyl Methyl Geranyl H H 50 Methyl Methyl H H H 51 Methyl Isopropyl H HH 52 Methyl Butyl H H H 53 Methyl Hexyl H H H 54 Methyl 2-Methyl-pentylH H H 55 Methyl Octyl H H H 56 Methyl 2-Propenyl H H H 57 Methyl GeranylH H H 58 Methyl H Methyl H H 59 Methyl H Butyl H H 60 Methyl H Hexyl H H61 Methyl H 3-Methyl- H H 2-butenyl 62 Methyl H Geranyl H H 63 Methyl HH H H 64 Ethyl Acetyl Methyl H H 65 Ethyl Acetyl Ethyl H H 66 EthylAcetyl Butyl H H 67 Ethyl Acetyl Hexyl H H 68 Ethyl Acetyl 3-Methyl- H H2-butenyl 69 Ethyl Acetyl Geranyl H H 70 Ethyl Acetyl H H H 71 EthylFormyl Methyl H H 72 Ethyl Formyl Butyl H H 73 Ethyl Formyl Hexyl H H 74Ethyl Formyl 3-Methyl- H H 2-butenyl 75 Ethyl Formyl Geranyl H H 76Ethyl Formyl H H H 77 Ethyl Methyl Methyl H H 78 Ethyl Methyl Butyl H H79 Ethyl Methyl Hexyl H H 80 Ethyl Methyl 3-Methyl- H H 2-butenyl

TABLE 3 Compound No . R₁ R₂ R₃ R₄ R₅ 81 Ethyl Methyl Geranyl H H 82Ethyl Methyl H H H 83 Ethyl Isopropyl H H H 84 Ethyl Butyl H H H 85Ethyl Hexyl H H H 86 Ethyl 2-Methyl-pentyl H H H 87 Ethyl Octyl H H H 88Ethyl 2-Propenyl H H H 89 Ethyl Geranyl H H H 90 Ethyl H Methyl H H 91Ethyl H Butyl H H 92 Ethyl H Hexyl H H 93 Ethyl H 3-Methyl- H H2-butenyl 94 Ethyl H Geranyl H H 95 Ethyl H H H H 96 Propyl H Methyl H H97 Propyl H Propyl H H 98 Propyl H Butyl H H 99 Propyl H Decyl H H 100Butyl Acetyl Methyl H H 101 Butyl Acetyl Ethyl H H 102 Butyl AcetylButyl H H 103 Butyl Acetyl Hexyl H H 104 Butyl Acetyl 3-Methyl- H H2-butenyl 105 Butyl Acetyl Geranyl H H 106 Butyl Acetyl H H H 107 ButylFormyl Methyl H H 108 Butyl Formyl Butyl H H 109 Butyl Formyl Hexyl H H110 Butyl Formyl 3-Methyl- H H 2-butenyl 111 Butyl Formyl Geranyl H H112 Butyl Formyl H H H 113 Butyl Methyl Methyl H H 114 Butyl MethylButyl H H 115 Butyl Methyl H H H 116 Butyl Isopropyl H H H 117 ButylButyl H H H 118 Butyl Hexyl H H H 119 Butyl 2-Methyl-pentyl H H H 120Butyl Octyl H H H

TABLE 4 Compound No. R₁ R₂ R₃ R₄ R₅ 121 Butyl 2-Propenyl H H H 122 ButylGeranyl H H H 123 Butyl H Methyl H H 124 Butyl H Butyl H H 125 Butyl HHexyl H H 126 Butyl H 3-Methyl- H H 2-butenyl 127 Butyl H Geranyl H H128 Butyl H H H H 129 Hexyl Acetyl Methyl H H 130 Hexyl Acetyl Ethyl H H131 Hexyl Acetyl Butyl H H 132 Hexyl Acetyl Hexyl H H 133 Hexyl Acetyl3-Methyl- H H 2-butenyl 134 Hexyl Acetyl Geranyl H H 135 Hexyl Acetyl HH H 136 Hexyl Formyl Methyl H H 137 Hexyl Formyl Butyl H H 138 HexylFormyl Hexyl H H 139 Hexyl Formyl 3-Methyl- H H 2-butenyl 140 HexylFormyl Geranyl H H 141 Hexyl Formyl H H H 142 Hexyl Methyl Methyl H H143 Hexyl Methyl Butyl H H 144 Hexyl Methyl H H H 145 Hexyl Isopropyl HH H 146 Hexyl Butyl H H H 147 Hexyl Hexyl H H H 148 Hexyl2-Methyl-pentyl H H H 149 Hexyl Octyl H H H 150 Hexyl 2-Propenyl H H H151 Hexyl Geranyl H H H 152 Hexyl H Methyl H H 153 Hexyl H Butyl H H 154Hexyl H Hexyl H H 155 Hexyl H 3-Methyl- H H 2-butenyl 156 Hexyl HGeranyl H H 157 Hexyl H H H H 158 Octyl Acetyl Methyl H H 159 OctylAcetyl Ethyl H H 160 Octyl Acetyl Butyl H H

TABLE 5 Compound No. R₁ R₂ R₃ R₄ R₅ 161 Octyl Acetyl Hexyl H H 162 OctylAcetyl 3-Methyl- H H 2-butenyl 163 Octyl Acetyl Geranyl H H 164 OctylAcetyl H H H 165 Octyl Formyl Methyl H H 166 Octyl Formyl Butyl H H 167Octyl Formyl Hexyl H H 168 Octyl Formyl 3-Methyl- H H 2-butenyl 169Octyl Formyl Geranyl H H 170 Octyl Formyl H H H 171 Octyl Methyl MethylH H 172 Octyl Methyl Butyl H H 173 Octyl Methyl H H H 174 OctylIsopropyl H H H 175 Octyl Butyl H H H 176 Octyl Hexyl H H H 177 Octyl2-Methyl-pentyl H H H 178 Octyl Octyl H H H 179 Octyl 2-Propenyl H H H180 Octyl Geranyl H H H 181 Octyl H Methyl H H 182 Octyl H Butyl H H 183Octyl H Hexyl H H 184 Octyl H 3-Methyl- H H 2-butenyl 185 Octyl HGeranyl H H 186 Octyl H H H H 187 H Acetyl Methyl H Hexyl 188 H AcetylButyl H Hexyl 189 H Acetyl Hexyl H Hexyl 190 H Acetyl 3-Methyl- H Hexyl2-butenyl 191 H Acetyl Geranyl H Hexyl 192 H Acetyl H H Hexyl 193 HFormyl Methyl H Hexyl 194 H Formyl Butyl H Hexyl 195 H Formyl Hexyl HHexyl 196 H Formyl 3-Methyl- H Hexyl 2-butenyl 197 H Formyl Geranyl HHexyl 198 H Formyl H H Hexyl 199 H Methyl Methyl H Hexyl 200 H MethylButyl H Hexyl

TABLE 6 Compound No. R₁ R₂ R₃ R₄ R₅ 201 H Methyl Hexyl H Hexyl 202 HMethyl 3-Methyl- H Hexyl 2-butenyl 203 H Methyl Geranyl H Hexyl 204 HMethyl H H Hexyl 205 H Isopropyl H H Hexyl 206 H Butyl H H Hexyl 207 HHexyl H H Hexyl 208 H 2-Methyl-pentyl H H Hexyl 209 H Octyl H H Hexyl210 H 2-Propenyl H H Hexyl 211 H Geranyloxy H H Octyl 212 H H H H Octyl213 H H Methyl H Octyl 214 H H Butyl H Octyl 215 H H Hexyl H Octyl 216 HH 3-Methyl- H Octyl 2-butenyl 217 H H Geranyl H Octyl 218 Methyl AcetylMethyl H Ethyl 219 Methyl Acetyl Ethyl H Ethyl 220 Methyl Acetyl Butyl HEthyl 221 Methyl Acetyl Hexyl H Ethyl 222 Methyl Acetyl 3-Methyl- HEthyl 2-butenyl 223 Methyl Acetyl Geranyl H Ethyl 224 Methyl Acetyl H HEthyl 225 Methyl Formyl Methyl H Ethyl 226 Methyl Formyl Butyl H Ethyl227 Methyl Formyl Hexyl H Ethyl 228 Methyl Formyl 3-Methyl- H Ethyl2-butenyl 229 Methyl Formyl Geranyl H Ethyl 230 Methyl Formyl H H Ethyl231 Methyl Methyl Methyl H Ethyl 232 Methyl Methyl Butyl H Ethyl 233Methyl Methyl Hexyl H Ethyl 234 Methyl Methyl 3-Methyl- H Ethyl2-butenyl 235 Methyl Methyl Geranyl H Ethyl 236 Methyl Methyl H H Ethyl237 Methyl Isopropyl H H Ethyl 238 Methyl Butyl H H Ethyl 239 MethylHexyl H H Ethyl 240 Methyl 2-Methyl-pentyl H H Ethyl

TABLE 7 Compound No. R₁ R₂ R₃ R₄ R₅ 241 Methyl Octyl H H Ethyl 242Methyl 2-Propenyl H H Ethyl 243 Methyl Geranyl H H Ethyl 244 Methyl HMethyl H Ethyl 245 Methyl H Butyl H Ethyl 246 Methyl H Hexyl H Ethyl 247Methyl H 3-Methyl- H Ethyl 2-butenyl 248 Methyl H Geranyl H Ethyl 249Methyl H H H Ethyl 250 Ethyl Acetyl Methyl H Butyl 251 Ethyl AcetylEthyl H Butyl 252 Ethyl Acetyl Butyl H Butyl 253 Ethyl Acetyl Hexyl HButyl 254 Ethyl Acetyl 3-Methyl- H Butyl 2-butenyl 255 Ethyl AcetylGeranyl H Butyl 256 Ethyl Acetyl H H Butyl 257 Ethyl Formyl Methyl HButyl 258 Ethyl Formyl Butyl H Butyl 259 Ethyl Formyl Hexyl H Butyl 260Ethyl Formyl 3-Methyl- H Butyl 2-butenyl 261 Ethyl Formyl Geranyl HButyl 262 Ethyl Formyl H H Butyl 263 Ethyl Methyl Methyl H Butyl 264Ethyl Methyl Butyl H Butyl 265 Ethyl Methyl Hexyl H Butyl 266 EthylMethyl 3-Methyl- H Butyl 2-butenyl 267 Ethyl Methyl Geranyl H Butyl 268Ethyl Methyl H H Butyl 269 Ethyl Isopropyl H H Butyl 270 Ethyl Butyl H HButyl 271 Ethyl Hexyl H H Butyl 272 Ethyl 2-Methyl-pentyl H H Butyl 273Ethyl Octyl H H Butyl 274 Ethyl 2-Propenyl H H Butyl 275 Ethyl Geranyl HH Butyl 276 Ethyl H Methyl H Butyl 277 Ethyl H Butyl H Butyl 278 Ethyl HHexyl H Butyl 279 Ethyl H 3-Methyl- H Butyl 2-butenyl 280 Ethyl HGeranyl H Butyl

TABLE 8 Compound No. R₁ R₂ R₃ R₄ R₅ 281 Ethyl H H H Butyl 282 Propyl HMethyl H Butyl 283 Propyl H Propyl H Butyl 284 Propyl H Butyl H Butyl285 Propyl H Decyl H Butyl 286 Butyl Acetyl Methyl H Methyl 287 ButylAcetyl Ethyl H Methyl 288 Butyl Acetyl Butyl H Methyl 289 Butyl AcetylHexyl H Methyl 290 Butyl Acetyl 3-Methyl- H Methyl 2-butenyl 291 ButylAcetyl Geranyl H Methyl 292 Butyl Acetyl H H Methyl 293 Butyl FormylMethyl H Methyl 294 Butyl Formyl Butyl H Methyl 295 Butyl Formyl Hexyl HMethyl 296 Butyl Formyl 3-Methyl- H Methyl 2-butenyl 297 Butyl FormylGeranyl H Methyl 298 Butyl Formyl H H Methyl 299 Butyl Methyl Methyl HMethyl 300 Butyl Methyl Butyl H Methyl 301 Butyl Methyl H Methyl Methyl302 Butyl Isopropyl H Methyl Methyl 303 Butyl Butyl H Methyl Methyl 304Butyl Hexyl H Methyl Methyl 305 Butyl 2-Methyl- H Methyl Methyl pentyl306 Butyl Octyl H Methyl Methyl 307 Butyl 2-Propenyl H Methyl Methyl 308Butyl Geranyl H Methyl Methyl 309 Butyl H Methyl Methyl Methyl 310 ButylH Butyl Methyl Methyl 311 Butyl H Hexyl Methyl Methyl 312 Butyl H3-Methyl- Methyl Methyl 2-butenyl 313 Butyl H Geranyl Methyl Methyl 314Butyl H H Methyl Methyl 315 Hexyl Acetyl Methyl H Ethyl 316 Hexyl AcetylEthyl H Ethyl 317 Hexyl Acetyl Butyl H Ethyl 318 Hexyl Acetyl Hexyl HEthyl 319 Hexyl Acetyl 3-Methyl- H Ethyl 2-butenyl 320 Hexyl AcetylGeranyl H Ethyl

TABLE 9 Compound No. R₁ R₂ R₃ R₄ R₅ 321 Hexyl Acetyl H H Ethyl 322 HexylFormyl Methyl H Ethyl 323 Hexyl Formyl Butyl H Ethyl 324 Hexyl FormylHexyl H Ethyl 325 Hexyl Formyl 3-Methyl-2-butenyl H Ethyl 326 HexylFormyl Geranyl H Ethyl 327 Hexyl Formyl H H Ethyl 328 Hexyl MethylMethyl H Ethyl 329 Hexyl Methyl Butyl H Ethyl 330 Hexyl Methyl H H Ethyl331 Hexyl Isopropyl H H Ethyl 332 Hexyl Butyl H H Ethyl 333 Hexyl HexylH H Ethyl 334 Hexyl 2-Methyl- H H Ethyl pentyl 335 Hexyl Octyl H H Ethyl336 Hexyl 2-Propenyl H H Ethyl 337 Hexyl Geranyl H H Ethyl 338 Hexyl HMethyl H Ethyl 339 Hexyl H Butyl H Ethyl 340 Hexyl H Hexyl H Ethyl 341Hexyl H 3-Methyl-2-butenyl H Ethyl 342 Hexyl H Geranyl H Ethyl 343 HexylH H H Ethyl 344 Octyl Acetyl Methyl H Ethyl 345 Octyl Acetyl Ethyl HEthyl 346 Octyl Acetyl Butyl H Ethyl 347 Octyl Acetyl Hexyl H Ethyl 348Octyl Acetyl 3-Methyl-2-butenyl H Ethyl 349 Octyl Acetyl Geranyl H Ethyl350 Octyl Acetyl H H Ethyl 351 Octyl Formyl Methyl H Ethyl 352 OctylFormyl Butyl H Ethyl 353 Octyl Formyl Hexyl H Ethyl 354 Octyl Formyl3-Methyl-2-butenyl H Ethyl 355 Octyl Formyl Geranyl H Ethyl 356 OctylFormyl H H Ethyl 357 Octyl Methyl Methyl H Ethyl 358 Octyl Methyl ButylH Ethyl 359 Octyl Methyl H H Ethyl 360 Octyl Isopropyl H H Ethyl

TABLE 10 Compound No. R₁ R₂ R₃ R₄ R₅ 361 Octyl Butyl H H Ethyl 362 OctylHexyl H H Ethyl 363 Octyl 2-Methyl- H H Ethyl pentyl 364 Octyl Octyl H HEthyl 365 Octyl 2-Propenyl H H Ethyl 366 Octyl Geranyl H H Ethyl 367Octyl H Methyl H Ethyl 368 Octyl H Butyl H Ethyl 369 Octyl H Hexyl HEthyl 370 Octyl H 3-Methyl-2-butenyl H Ethyl 371 Octyl H Geranyl H Ethyl372 Octyl H H H Ethyl 373 Methyl Acetyl Methyl Acetyl Ethyl 374 MethylAcetyl Ethyl Acetyl Ethyl 375 Methyl Acetyl Butyl Acetyl Ethyl 376Methyl Acetyl Hexyl Acetyl Ethyl 377 Methyl Acetyl 3-Methyl-2-butenylAcetyl Ethyl 378 Methyl Acetyl Geranyl Acetyl Ethyl 379 Methyl Acetyl HAcetyl Ethyl 380 Methyl Formyl Methyl Acetyl Ethyl 381 Methyl FormylButyl Acetyl Ethyl 382 Methyl Formyl Hexyl Acetyl Ethyl 383 MethylFormyl 3-Methyl-2-butenyl Acetyl Ethyl 384 Methyl Formyl Geranyl AcetylEthyl 385 Methyl Formyl H Acetyl Ethyl 386 Methyl Methyl Methyl H Acetyl387 Methyl Methyl Butyl H Acetyl 388 Methyl Methyl Hexyl H Acetyl 389Methyl Methyl 3-Methyl-2-butenyl H Acetyl 390 Methyl Methyl Geranyl HAcetyl 391 Methyl Methyl H H Acetyl 392 Methyl Isopropyl H H Acetyl 393Methyl Butyl H H Acetyl 394 Methyl Hexyl H H Acetyl 395 Methyl 2-Methyl-H H Acetyl pentyl 396 Methyl Octyl H H Acetyl 397 Methyl 2-Propenyl H HAcetyl 398 Methyl Geranyl H H Acetyl 399 Methyl H Methyl H Acetyl 400Methyl H Butyl H Acetyl

TABLE 11 Compound No. R₁ R₂ R₃ R₄ R₅ 401 Methyl H Hexyl H Acetyl 402Methyl H 3-Methyl- H Acetyl 2-butenyl 403 Methyl H Geranyl H Acetyl 404Methyl H H H Acetyl 405 Ethyl Acetyl Methyl H Acetyl 406 Ethyl AcetylEthyl H Acetyl 407 Ethyl Acetyl Butyl H Acetyl 408 Ethyl Acetyl Hexyl HAcetyl 409 Ethyl Acetyl 3-Methyl- H Acetyl 2-butenyl 410 Ethyl AcetylGeranyl H Acetyl 411 Ethyl Acetyl H H Acetyl 412 Ethyl Formyl Methyl HAcetyl 413 Ethyl Formyl Butyl H Acetyl 414 Ethyl Formyl Hexyl H Acetyl415 Ethyl Formyl 3-Methyl- H Acetyl 2-butenyl 416 Ethyl Formyl Geranyl HAcetyl 417 Ethyl Formyl H H Acetyl 418 Ethyl Methyl Methyl H Acetyl 419Ethyl Methyl Butyl H Acetyl 420 Ethyl Methyl Hexyl H Acetyl 421 EthylMethyl 3-Methyl- H Acetyl 2-butenyl 422 Ethyl Methyl Geranyl H Acetyl423 Ethyl Methyl H H Acetyl 424 Ethyl Isopropyl H H Acetyl 425 EthylButyl H H Acetyl 426 Ethyl Hexyl H H Acetyl 427 Ethyl 2-Methyl-pentyl HH Acetyl 428 Ethyl Octyl H H Acetyl 429 Ethyl 2-Propenyl H H Acetyl 430Ethyl Geranyl H H Acetyl 431 Ethyl H Methyl H Acetyl 432 Ethyl H Butyl HAcetyl 433 Ethyl H Hexyl H Acetyl 434 Ethyl H 3-Methyl- H Acetyl2-butenyl 435 Ethyl H Geranyl H Acetyl 436 Ethyl H H H Acetyl 437 PropylH Methyl H Acetyl 438 Propyl H Propyl H Acetyl 439 Propyl H Butyl HAcetyl 440 Propyl H Decyl H Acetyl

TABLE 12 Compound No. R₁ R₂ R₃ R₄ R₅ 441 Butyl Acetyl Methyl H Formyl442 Butyl Acetyl Ethyl H Formyl 443 Butyl Acetyl Butyl H Formyl 444Butyl Acetyl Hexyl H Formyl 445 Butyl Acetyl 3-Methyl- H Formyl2-butenyl 446 Butyl Acetyl Geranyl H Formyl 447 Butyl Acetyl H H Formyl448 Butyl Formyl Methyl H Formyl 449 Butyl Formyl Butyl H Formyl 450Butyl Formyl Hexyl H Formyl 451 Butyl Formyl 3-Methyl- H Formyl2-butenyl 452 Butyl Formyl Geranyl H Formyl 453 Butyl Formyl H H Formyl454 Butyl Methyl Methyl H Formyl 455 Butyl Methyl Butyl H Formyl 456Butyl Methyl H H Formyl 457 Butyl Isopropyl H H Formyl 458 Butyl Butyl HH Formyl 459 Butyl Hexyl H H Formyl 460 Butyl 2-Methyl-pentyl H H Formyl461 Butyl Octyl H H Formyl 462 Butyl 2-Propenyl H H Formyl 463 ButylGeranyl H H Formyl 464 Butyl H Methyl H Formyl 465 Butyl H Butyl HFormyl 466 Butyl H Hexyl H Formyl 467 Butyl H 3-Methyl- H Formyl2-butenyl 468 Butyl H Geranyl H Formyl 469 Butyl H H H Formyl 470 HexylAcetyl Methyl H Propionyl 471 Hexyl Acetyl Ethyl H Propionyl 472 HexylAcetyl Butyl H Propionyl 473 Hexyl Acetyl Hexyl H Propionyl 474 HexylAcetyl 3-Methyl- H Propionyl 2-butenyl 475 Hexyl Acetyl Geranyl HPropionyl 476 Hexyl Acetyl H H Propionyl 477 Hexyl Formyl Methyl HPropionyl 478 Hexyl Formyl Butyl H Propionyl 479 Hexyl Formyl Hexyl HPropionyl 480 Hexyl Formyl 3-Methyl- H Propionyl 2-butenyl

TABLE 13 Compound No. R₁ R₂ R₃ R₄ R₅ 481 Hexyl Formyl Geranyl HPropionyl 482 Hexyl Formyl H H Propionyl 483 Hexyl Methyl Methyl HPropionyl 484 Hexyl Methyl Butyl H Propionyl 485 Hexyl Methyl H HPropionyl 486 Hexyl Isopropyl H H Propionyl 487 Hexyl Butyl H HPropionyl 488 Hexyl Hexyl H H Propionyl 489 Hexyl 2-Methyl-pentyl H HPropionyl 490 Hexyl Octyl H H Propionyl 491 Hexyl 2-Propenyl H HPropionyl 492 Hexyl Geranyl H H Propionyl 493 Hexyl H Methyl H Propionyl494 Hexyl H Butyl H Propionyl 495 Hexyl H Hexyl H Propionyl 496 Hexyl H3-Methyl- H Propionyl 2-butenyl 497 Hexyl H Geranyl H Propionyl 498Hexyl H H H Propionyl 499 Octyl Acetyl Methyl H Propionyl 500 OctylAcetyl Ethyl H Benzoyl 501 Octyl Acetyl Butyl H Benzoyl 502 Octyl AcetylHexyl H Benzoyl 503 Octyl Acetyl 3-Methyl- H Benzoyl 2-butenyl 504 OctylAcetyl Geranyl H Benzoyl 505 Octyl Acetyl H H Benzoyl 506 Octyl FormylMethyl H Benzoyl 507 Octyl Formyl Butyl H Benzoyl 508 Octyl Formyl HexylH Benzoyl 509 Octyl Formyl 3-Methyl- H Benzoyl 2-butenyl 510 OctylFormyl Geranyl H Benzoyl 511 Octyl Formyl H H Benzoyl 512 Octyl MethylMethyl H Benzoyl 513 Octyl Methyl Butyl H Benzoyl 514 Methyl Methyl H HBenzoyl 515 Methyl Isopropyl H H Benzoyl 516 Methyl Butyl H H Benzoyl517 Methyl Hexyl H H Benzoyl 518 Methyl 2-Methyl-pentyl H H Benzoyl 519Methyl Octyl H H Benzoyl 520 Methyl 2-Propenyl H H Benzoyl

TABLE 14 Compound No. R₁ R₂ R₃ R₄ R₅ 521 Methyl Geranyl H H Benzoyl 522Butyl H Methyl H Benzoyl 523 Butyl H Butyl H Benzoyl 524 Butyl H Hexyl HBenzoyl 525 Butyl H 3-Methyl- H Benzoyl 2-butenyl 526 Butyl H Geranyl HBenzoyl 527 Butyl H H H Benzoyl 528 Methyl Acetyl Methyl H Cinnamoyl 529Methyl Acetyl Ethyl H Cinnamoyl 530 Methyl Acetyl Butyl H Cinnamoyl 531Methyl Acetyl Hexyl H Cinnamoyl 532 Methyl Acetyl 3-Methyl- H Cinnamoyl2-butenyl 533 Methyl Acetyl Geranyl H Cinnamoyl 534 Methyl Acetyl H HCinnamoyl 535 Methyl H Methyl H Cinnamoyl 536 Methyl H Butyl H Cinnamoyl537 Methyl H Hexyl H Cinnamoyl 538 Methyl H 3-Methyl- H Cinnamoyl2-butenyl 539 Methyl H Geranyl H Cinnamoyl 540 Methyl H H H Cinnamoyl541 Methyl Methyl Methyl H 3,5-Dimethoxy-4- hydroxycinnamoyl 542 MethylMethyl Butyl H 3,5-Dimethoxy-4- hydroxycinnamoyl 543 Methyl Methyl HexylH 3,5-Dimethoxy-4- hydroxycinnamoyl 544 Methyl Methyl 3-Methyl- H3,5-Dimethoxy-4- 2-butenyl hydroxycinnamoyl 545 Methyl Methyl Geranyl H3,5-Dimethoxy-4- hydroxycinnamoyl 546 Methyl Methyl H H 3,5-Dimethoxy-4-hydroxycinnamoyl 547 Methyl Isopropyl H H 3,5-Dimethoxy-4-hydroxycinnamoyl 548 Methyl Butyl H H 3,5-Dimethoxy-4- hydroxycinnamoyl549 Methyl Hexyl H H 3,5-Dimethoxy-4- hydroxycinnamoyl 550 Methyl2-Methyl- H H 3,5-Dimethoxy-4- pentyl hydroxycinnamoyl

TABLE 15 Compound No. R₁ R₂ R₃ R₄ R₅ 551 Methyl Octyl H H3,5-Dimethoxy-4- hydroxycinnamoyl 552 Methyl 2-Propenyl H H3,5-Dimethoxy-4- hydroxycinnamoyl 553 Methyl Geranyl H H3,5-Dimethoxy-4- hydroxycinnamoyl 554 Methyl H Methyl H 3,5-Dimethoxy-4-hydroxycinnamoyl 555 Methyl H Butyl H 3,5-Dimethoxy-4- hydroxycinnamoyl556 Methyl H Hexyl H 3,5-Dimethoxy-4- hydroxycinnamoyl 557 Methyl H3-Methyl- H 3,5-Dimethoxy-4- 2-butenyl hydroxycinnamoyl 558 Methyl HGeranyl H 3,5-Dimethoxy-4- hydroxycinnamoyl 559 Methyl H H H 3,5-Dimethoxy-4- hydroxycinnamoyl 560 Ethyl Acetyl Methyl H 4-Hydroxy-3-methoxycinnamoyl 561 Ethyl Acetyl Ethyl H 4-Hydroxy-3- methoxycinnamoyl562 Ethyl Acetyl Butyl H 4-Hydroxy-3- methoxycinnamoyl 563 Ethyl AcetylHexyl H 4-Hydroxy-3- methoxycinnamoyl 564 Ethyl Acetyl 3-Methyl- H4-Hydroxy-3- 2-butenyl methoxycinnamoyl 565 Ethyl Acetyl Geranyl H4-Hydroxy-3- methoxycinnamoyl 566 Ethyl Acetyl H H 4-Hydroxy-3-methoxycinnamoyl 567 Ethyl Formyl Methyl H 4-Hydroxy-3- methoxycinnamoyl568 Ethyl Formyl Butyl H 4-Hydroxy-3- methoxycinnamoyl 569 Ethyl FormylHexyl H 4-Hydroxy-3- methoxycinnamoyl 570 Ethyl Formyl 3-Methyl- H4-Hydroxy-3- 2-butenyl methoxycinnamoyl

TABLE 16 Compound No. R₁ R₂ R₃ R₄ R₅ 571 Ethyl Formyl Geranyl H4-Hydroxy-3- methoxycinnamoyl 572 Ethyl Formyl H H 4-Hydroxy-3-methoxycinnamoyl 573 Methyl Methyl Methyl H 4-Hydroxy-3-methoxycinnamoyl 574 Methyl Methyl Butyl H 4-Hydroxy-3- methoxycinnamoyl575 Methyl Methyl Hexyl H 4-Hydroxy-3- methoxycinnamoyl 576 MethylMethyl 3-Methyl-2- H 4-Hydroxy-3- butenyl methoxycinnamoyl 577 MethylMethyl Geranyl H 4-Hydroxy-3- methoxycinnamoyl 578 Methyl Methyl H H4-Hydroxy-3- methoxycinnamoyl 579 Methyl Isopropyl H H 4-Hydroxy-3-methoxycinnamoyl 580 Methyl Butyl H H 4-Hydroxy-3- methoxycinnamoyl 581Methyl Hexyl H H 4-Hydroxy-3- methoxycinnamoyl 582 Methyl 2-Methyl- H H4-Hydroxy-3- pentyl methoxycinnamoyl 583 Methyl Octyl H H 4-Hydroxy-3-methoxycinnamoyl 584 Methyl 2-Propenyl H H 4-Hydroxy-3- methoxycinnamoyl585 Methyl Geranyl H H 4-Hydroxy-3- methoxycinnamoyl 586 Methyl H MethylH Benzyl 587 Methyl H Butyl H Benzyl 588 Methyl H Hexyl H Benzyl 589Methyl H 3-Methyl-2- H Benzyl butenyl 590 Methyl H Geranyl H Benzyl 591Methyl H H H Benzyl 592 Propyl H Methyl H Benzyl 593 Propyl H Propyl HBenzyl 594 Propyl H Butyl H Benzyl 595 Propyl H Decyl H Benzyl

TABLE 17 Compound No. R₁ R₂ R₃ R₄ R₅ 596 Methyl Methyl H H 2-Propenyl597 Methyl Isopropyl H H 2-Propenyl 598 Methyl Butyl H H 2-Propenyl 599Methyl Hexyl H H 2-Propenyl 600 Methyl 2-Methyl- H H 2-Propenyl pentyl601 Methyl Octyl H H 2-Propenyl 602 Methyl 2-Propenyl H H 2-Propenyl 603Methyl Geranyl H H 2-Propenyl 604 Methyl H Methyl H 2-Propenyl 605Methyl H Butyl H 2-Propenyl 606 Methyl H Hexyl H 2-Propenyl 607 Methyl H3-Methyl- H 2-Propenyl 2-butenyl 608 Methyl H Geranyl H 2-Propenyl 609Methyl H H H 2-Propenyl 610 Methyl H Methyl H 2-Propenyl 611 Methyl HPropyl H 2-Propenyl 612 Methyl H Butyl H 2-Propenyl 613 Methyl H Decyl H2-Propenyl 614 Methyl Methyl H H Geranyl 615 Methyl Isopropyl H HGeranyl 616 Methyl Butyl H H Geranyl 617 Methyl Hexyl H H Geranyl 618Methyl 2-Methyl- H H Geranyl pentyl 619 Methyl Octyl H H Geranyl 620Methyl 2-Propenyl H H Geranyl 621 Methyl Geranyl H H Geranyl 622 MethylH Methyl H Geranyl 623 Methyl H Butyl H Geranyl 624 Methyl H Hexyl HGeranyl 625 Methyl H 3-Methyl- H Geranyl 2-butenyl 626 Methyl H GeranylH Geranyl 627 Methyl H H H Geranyl 628 Methyl H Methyl H Geranyl 629Methyl H Propyl H Geranyl 630 Methyl H Butyl H Geranyl

In the present invention, physiologically acceptable salts of thesecompounds are also included. As used herein, physiologically acceptablesalts refer to alkali addition salts having no toxicity with respect tocompounds having a hydroxyl group, especially compounds having ahydroxyl group at the 3- and/or 4-positions among the above-describedcompounds, and examples thereof include nontoxic salts such as sodiumsalt, potassium salt, magnesium salt, calcium salt, ammonium salt andnontoxic amine salt. These salts can be prepared by a conventionallyknown method.

With respect to the compound having no hydroxyl group, there can beexemplified nontoxic addition salts prepared by reacting an amino groupof an aromatic ring with mineral acids such as hydrochloric acid,sulfuric acid and phosphoric acid, or various organic acids such asacetic acid, propionic acid, succinic acid, tartaric acid, maleic acidand fumaric acid, or sulfonic acids such as methanesulfonic acid. Thesesalts can be prepared by a conventionally known method.

As described in the examples described hereinafter, the7-aminoquinolinone derivative and its physiologically acceptable saltthereof in the present invention have low toxicity and are extremelyuseful as a therapeutic agent for chronic obstructive pulmonary diseasefor treating or preventing various chronic obstructive pulmonarydiseases.

Chronic obstructive pulmonary disease as used herein refers to lungdiseases including chronic bronchitis and pulmonary emphysema. Chronicobstructive pulmonary disease is generally characterized by progressiveand irreversible airflow limitation. In many cases, it is accompanied byairway hyper-responsiveness and some chronic obstructive pulmonarydisease is reversible symptom. Chronic bronchitis is characterized bychronic moist cough for 3 or more consecutive months in each ofconsecutive 2 years. Pulmonary emphysema is an permanent abnormalswelling of alveoli distal to terminal bronchiole, which is accompaniedby destructive changes of pulmonary alveolus walls and having no obviousfibrosis. Destructive change is defined as irregular swelling ofrespiratory air spaces, wherein regular appearances of pulmonaryacinuses and its components may be destroyed and disappeared.

As described above, chronic obstructive pulmonary disease ischaracterized by irreversible airflow limitation and has a pathologiccharacteristic different from asthma, which is a reversible airflowlimitation. Furthermore, in international asthma therapy guideline,“Guideline for the Diagnosis and Management of Asthma (NHLBI, 2002)”,inhalation steroids for drug treatment against bronchial asthma arerecommended as a first choice and its excellent effectiveness isconfirmed. However, in the similar global guideline, Global initiativefor chronic obstructive lung disease (GOLD; NHLBI/WHO, 1998), the effectof steroids on chronic obstructive pulmonary disease is a little andtherefore its use is not recommended well. Thus, chronic obstructivepulmonary disease and bronchial asthma have different responses todrugs.

Main therapy for chronic obstructive pulmonary disease is use ofbronchodilator such as anticholinergic agents and β-receptor agonists,wherein a symptomatic therapy for relaxing temporarily airwayobstructive state is carried out. Recently, research and development ofa long-acting anticholinergic agent and β receptor agonist has beencarried out, but any of them belongs to a symptomatic therapy. The riskfactor of chronic obstructive pulmonary disease is noxious microparticles due to smoking and air pollution. It is believed that lastingchronic inflammation state in peripheral respiratory tract and pulmonaryalveoli due to long-term exposure of them is the cause for the diseasedevelopment. That is, the above mentioned GOLD describes clearly thatthere is observed neutrophilic inflammation in a lung and that importantone as its causal and progressive factor is inflammation due toimbalance between a protease and a protease inhibitor, and oxidativestress. However, any agents capable of treating chronic obstructivepulmonary disease by suppressing such inflammation have never beenmarketed.

The present inventors have paid attention to airway inflammation due tooxidative stress, which is considered to as an important factor for theonset of chronic obstructive pulmonary disease, made an animal modelcorresponding to chronic obstructive pulmonary disease and intensivelystudied about a drug capable of treating airway inflammation in themodel. Consequently, they have found a compound which exerts a potenttherapeutic effect in a model in which the airway is exposed toperoxynitrite, a potent oxidant produced in the body described in GOLD,to induce airway hyper-responsiveness.

It is suggested that chronic obstructive pulmonary disease is alsoinvolved in air pollution substances and it is known that, when exposinganimals such as rat and guinea pig to ozone, one of air pollutionsubstances, airway inflammation, including airway hyper-responsiveness,similar to chronic obstructive pulmonary disease is induced. Therefore,the present inventors have investigated effectiveness of the compoundsof the present invention against a test model in which airwayhyper-responsiveness is induced by exposure of ozone to guinea pig, andthus obtaining such a finding that the compounds of the presentinvention have equal or greater effectiveness than that of theconventional agents and are therefore extremely useful as a agent forchronic obstructive pulmonary disease.

The therapeutic agent for chronic obstructive pulmonary disease of thepresent invention can be administered orally (taken internally orinhaled) or parenterally (e.g., intravenous administration, subcutaneousadministration, transcutaneous administration or intrarectaladministration), and can be prepared into a formulation form suitablefor the respective administration method at the time of administration.

The formulation can be prepared in various formulation forms such astablets, capsules, granules, grains, powders, troches, sublingualformulations, suppositories, ointments, injections, emulsions,suspensions and syrups according to the specific application.

When preparing these formulations, said formulations can be formulatedin accordance with known methods using non-toxic additives normally usedin this type of formulation, examples of which include vehicles,binders, disintegration agents, lubricants, preservatives, antioxidants,isotonic agents, buffers, coating agents, correctives, dissolvingassistants, bases, dispersants, stabilizers and colorants. Specificexamples of these nontoxic additives are listed below.

Examples of vehicles include starch and its derivatives (such as dextrinand carboxymethyl starch), cellulose and its derivatives (such as methylcellulose and hydroxypropyl cellulose), saccharides (such as lactose,refined sugar and glucose), silicic acid and silicates (such asnaturally-occurring aluminum silicate and magnesium silicate),carbonates (such as calcium carbonate, magnesium carbonate, and sodiumhydrogen carbonate), aluminum-magnesium hydroxide, synthetichydrotalcite, polyoxythylene derivatives, glycerin monostearate andsorbitan monooleate.

Examples of binders include starch and its derivatives (such aspregelatinized starch and dextrin), cellulose and its derivatives (suchas ethyl cellulose, sodium carboxymethyl cellulose andhydroxypropylmethyl cellulose), gum arabic, tragacanth gum, gelatin,saccharides (such as glucose and refined sugar), ethanol and polyvinylalcohol.

Examples of disintegration agents include starch and its derivatives(such as carboxymethyl starch and hydroxypropyl starch), cellulose andits derivatives (such as sodium carboxymethyl cellulose, crystalcellulose and hydroxypropylmethyl cellulose), carbonates (such ascalcium carbonate and calcium hydrogen carbonate), tragacanth gum,gelatin and agar.

Examples of lubricants include stearic acid, calcium stearate, magnesiumstearate, talc, silicic acid and its salts (such as light silicicanhydride and naturally-occurring aluminum silicate), titanium oxide,calcium hydrogen phosphate, dry aluminum hydroxide gel and macrogall.

Examples of preservatives include paraoxybenzoate esters, sulfites (suchas sodium sulfite and sodium pyrosulfite), phosphates (such as sodiumphosphate, calcium polyphosphate, sodium polyphosphate and sodiummetaphosphate), alcohols (such as chlorobutanol and benzyl alcohol),benzalkonium chloride, benzetonium chloride, phenol, cresol,chlorocresol, dehydroacetic acid, sodium dehydroacetate, glycerinsorbate and saccharides.

Examples of antioxidants include sulfites (such as sodium sulfite andsodium hydrogen sulfite), rongalite, erysorbic acid, L-ascorbic acid,cysteine thioglycerol, butylhydroxy anisole, dibutylhydroxy toluene,propyl gallate, ascorbic palmitate and d1-α-tocopherol.

Examples of isotonic agents include sodium chloride, sodium nitrate,potassium nitrate, dextrin, glycerin and glucose. In addition, examplesof buffers include sodium carbonate, hydrochloric acid, boric acid andphosphates (such as sodium hydrogen phosphate).

Examples of coating agents include cellulose derivatives (such ashydroxypropyl cellulose, cellulose acetophthalate and hydroxypropylmethyl cellulose phthalate), shellac, polyvinyl pyrrolidone, polyvinylpyridines (such as poly-2-vinylpyridine andpoly-2-vinyl-5-ethylpyridine), polyvinylacetyldiethylaminoacetate,polyvinyl alcohol phthalate and methacrylate-methacrylic acid copolymer.

Examples of correctives include saccharides (such as glucose, refinedsugar and lactose), sodium saccharine and sugar-alcohols. Examples ofdissolving assistants include ethylenediamine, nicotinic amide, sodiumsaccharine, citric acid, citrates, sodium benzoate, soaps, polyvinylpyrrolidone, polysorbates, sorbitan fatty acid esters, glycerin,polypropylene glycol and benzyl alcohol.

Examples of bases include fats (such as lard), vegetable oils (such asolive oil and sesame oil), animal oils, lanolinic acid, vaseline,paraffin, wax, resin, bentonite, glycerin, glycolic oil and higheralcohols (such as stearyl alcohol and cetanol).

Examples of dispersants include gum arabic, tragacanth gum, cellulosederivatives (such as methyl cellulose), stearate polyesters, sorbitansesquioleates, aluminum monostearate, sodium alginate, polysorbates andsorbitan fatty acid esters. In addition, examples of stabilizers includesulfites (such as sodium bisulfite), nitrogen and carbon dioxide.

In addition, although the content of the 7-aminoquinolinone derivativeand its physiologically acceptable salt thereof in this formulationvaries according to the formulation form. In general, it is preferablycontained at the concentration of 0.01 to 100% by weight.

Although the dose of the therapeutic agent for chronic obstructivepulmonary disease of the present invention can be varied over a widerange according to the target species of warm-blooded animal includinghumans, the severity of the symptoms and the diagnosis of a physician.In general, in the case of oral administration, the dose as the amountof active ingredient is from 0.01 to 50 mg, and preferably from 0.05 to10 mg, per day per 1 kg of body weight.

In the case of parenteral administration, the dose as the amount ofactive ingredient is from 0.01 to 10 mg, and preferably from 0.01 to 5mg, per day per 1 kg of body weight. In addition, the above dose can beadministered in a single administration or divided into severaladministrations, and can be suitably varied according to the severity ofpatient symptoms and diagnosis of a physician.

EXAMPLES

The following examples are intended to illustrate the present invention,but the scope of the present invention is not limited by the followingexamples.

Example 1 Acute Toxicity Test in Mice

This test was performed so as to investigate safety of the quinolinonederivatives of the present invention. The test procedure will now bedescribed.

(Test Procedure)

Each of 7-aminoquinolinone derivatives (compounds 32, 53, 55, 56, 58,87, 147, 173, 181, 204, 236, 276, 303, 309, 330, 359, 396, 401, 459,514, 519, 546 to 556, and 581) was forcibly administered orally at thedoses of 1000 and 2000 mg/kg to male ICR mice (body weight is 20 to 25g, 5 mice per one group), using feeding tubes for mice.

After the administration, the animals were kept in cages for 7 days.Then, general symptoms were observed and the number of dead animals wascounted. 50% lethal dose (LD₅₀: mg/kg) was extrapolated from themortality at 7th day after administration. As a result, the LD₅₀ of allaminoquinolinone derivatives was 1000 mg/kg or more, and therefore itwas clearly demonstrated that the aminoquinolinone derivatives of thepresent invention have extremely high safety.

Example 2

This test was performed so as to investigate the pharmacological effectof the 7-aminoquinolinone derivative of the present invention on anairway hyper-responsiveness model induced by exposure of peroxynitritein guinea pigs. The test procedure will now be described.

(Preparation of Airway Hyper-Responsiveness Model)

Guinea pigs were fasted for 18 hours or more. The animals wereadministrated the test substance (30 mg/kg) orally one hour beforeexposure of peroxynitrite and the neck was dissected under etheranesthesia, and then the trachea was exposed. 0.1 mL of 1 mmol/Lperoxynitrite was administered intratracheally into pulmonary side bypushing with air and, after the administration, the incision was suturedand disinfected.

(Measurement of Airway Hyper-Responsiveness to Histamine)

The measurement of airway hyper-responsiveness was performed on 5-day,taking the day of model preparation 0-day. Guinea pigs were fasted for18 hours or more. The measurement of lung resistance; (RLung) wasperformed according to the method of R. E. Giles et al. (R. E. Giles, M.P. Finkel and J. Mazurowski: Use of an Analog On-Line Computer for theEvaluation of Pulmonary Resistance and Dynamic Compliance in theAnesthetized Dog. Arch. Int. Pharmacodyn. 194, 213-222 (1971)). That is,the animals were anesthetized with Nembutal (Trade name: 40 mg/kg, i.v.,sodium pentobarbital) and subjected to cannulation into esophagus,trachea and jugular veins (for administration of histamine). Theesophagus and trachea cannulas were connected to an artificialrespirator (ventilation volume: 6 mL/kg, ventilation frequency: 60times/min, SN-480-7) and the Rlung was measured after intravenousadministration (dose of 0.1 mL/kg) of physiological saline solution andhistamine (32 μg/kg) using a total plethysmograph system via flowsensor, connected to Validyne DF45F (for flow rate) and DP45P (forpressure). RLung before administration was determined by averagingvalues of any 3 out of 20 breaths, RLung after administration ofphysiological saline solution was determined by averaging values of any3 out of 5 breaths, and RLung after administration of histamine wasdetermined by averaging values of the following 3 breaths; 1) showingthe maximum lung resistance, 2) taken just before and 3) taken justafter the one with the maximum lung resistance, out less than 20breaths. (The extreme values in RLung that occurred when animal movedduring the measurement were excluded from the calculations.)

The percentage of increase in lung resistance was calculated by thefollowing equation.

Increase in lung resistance (%)=([RLung after administration ofhistamine]−[RLung before administration])/[RLung beforeadministration]×100

TABLE 18 Increase in lung resistance (%) Compound Increase (%) CompoundIncrease (%) 32 435 359 431 53 440 396 421 55 425 401 420 56 434 459 42758 423 514 434 87 432 519 440 147 429 546 422 173 430 549 423 181 425551 416 204 439 553 417 236 428 556 426 276 430 581 430 303 427 Controlgroup 759 309 435 Non-stimulation group 382 330 417

From the above results, it was demonstrated that the 7-aminoquinolinonederivatives of the present invention inhibited the resistance to almostthe same degree to the non-stimulation group as compared with a controlgroup to which the test substance was not administered. Therefore, it isclear that the 7-aminoquinolinone derivatives of the present inventioninhibit an increase in lung resistance induced by peroxynitriteexposure.

Example 3

This test was performed by estimating the antioxidative effect of thetest substance using peroxynitrite quantitative method as a test systemwith dihydrorhodamine 123 so as to confirm the ability of the7-aminoquinolinone derivatives of the present invention to scavengeperoxynitrite. This is a method described in NITRIC OXIDE: Biology andChemistry Vol. 1, 145-157, 1997.

The test procedure will now be described.

(Preparation of the Test Substances and Reagents) 1. Preparation of TestSubstances

The test substance was weighted in an amount of approximately 10 mg,dissolved in a 10% Tween 80 solution and adjusted to 5×10⁻³ mol/L. Then,the solution was diluted with 0.1 mol/L phosphate buffer (pH=7.4) to5×10⁻⁴ mol/L. The diluent was further diluted stepwise with a phosphatebuffer containing 1% Tween 80 to obtain substance solution. Thepreparation was conducted before use. The final concentration of thetest substance was adjusted to 3×10⁻⁶, 1×10⁻⁶, 3×10⁻⁷, 1×10⁻⁷, and3×10⁻⁸ mol/L, respectively.

2. Preparation of Peroxynitrite Solution 1) Measurement of PeroxynitriteConcentration

To 20 μL of peroxynitrite solution (manufactured by DOJINDOLABORATORIES), 1980 μL of 0.1 mol/L sodium hydroxide was added and themixture was diluted 100 times. The absorbance of the maximum absorptionwavelength near 300 nm was measured using a UV-visible spectrophotometerand the concentration was calculated according to the followingequation.

Concentration (mmol/L)=(absorbance/1670)×100×1000

Based on the concentration calculated in the above section, dilutionwith a 0.1 mol/L sodium hydroxide solution was conducted and adjusted to10 mmol/L. 990 μL of a 0.1 mol/L sodium hydroxide solution was takeninto a 1.5 mL-Eppen tube. To the Eppen tube, 10 μL of a solutionadjusted to 10 mmol/L was added to prepare a 100 μmol/L solution.

3. Preparation of Dihydrorhodamine 123 Solution 1) 25 Mmol/LDihydrorhodamine 123 Stock Solution

Dihydrorhodamine 123 was dissolved into 1.155 mL of dimethylsulfoxide,and adjusted to the concentration of 25 mmol/L. This solution wasdispensed into 20 μL aliquots and then the aliquots were stored in abiomedical freezer (about −20° C.) and used as a stock solution.

2) Preparation of 500 nmol/L Dihydrorhodamine 123 Solution

To 490 μL of 0.02% Tween 80 containing 0.1 mol/L phosphate buffer, 10 μLof 25 mmol/L of a thawed dihydrorhodamine 123 stock solution was addedto make 500 μmol/L. The prepared solution was diluted with 0.1 mol/Lphosphate buffer (pH=7.4) 1000 times to prepare 500 nmol/L of adihydrorhodamine 123 solution.

(Measurement of Peroxynitrite Scavenging Activity) 1. Reaction Operation

(1) To a 3.5 mL brown vial containing a stirring bar, 1470 μL of a 500nmol/L dihydrorhodamine 123 solution and then 15 μL of the testsubstance solution was added. For the blank and control groups, 15 μL of0.1 mol/L phosphate buffer containing 1% Tween 80, as a solvent for thetest substance solution, was added. After the addition, the mixture wasstirred with a stirrer for 30 minutes.

15 μL of a 100 μmol/L peroxynitrite solution was added while stirring.For the blank group, 15 μL of a 0.1 mol/L sodium hydroxide solution wasadded. After stirring for 15 minutes, fluorescence intensity wasmeasured.

2. Measurement of Fluorescence Intensity

Fluorescence intensity of the reaction solution was measured using aspectrophotofluorometer under the following measuring conditions:excitation wavelength, 500 nm; emission wavelength, 536 nm; measuringtimes, one; response, 1 sec; photomultiplier tube voltage, Low; bandwidth at excitation side, 10 nm; bandwidth at emission side, 10 nm.

3. Calculation of Oxidation Rate of Dihydrorhodamine 123

The oxidation rate of dihydrorhodamine 123 when adding the testsubstance was calculated, taking the oxidation rate of dihydrorhodamine123 for control as 100, according to the following equation:

Oxidation rate (%) of dihydrorhodamine 123=(measured value for eachgroup−measured value for blank)/(measured for control−measured value forblank)×100

Calculation of Oxidation Inhibition Concentration (IC₅₀)

50% oxidation concentration, that is 50% oxidation inhibitionconcentration (IC₅₀) was calculated by giving a straight line from twopoints surrounding 50% oxidation rate.

The results are shown in the following table.

TABLE 19 50% Inhibitory concentration on oxidation (IC₅₀) ConcentrationConcentration Compound (μmol/L) Compound (μmol/L) 32 0.96 330 0.79 530.88 359 0.85 55 0.96 396 0.94 56 1.05 401 1.01 58 0.81 459 0.94 87 0.84514 0.91 147 0.79 519 0.83 173 0.89 546 0.79 181 0.94 549 0.80 204 0.89551 0.71 236 0.88 553 0.98 276 0.82 556 0.89 303 0.84 581 0.76 309 0.80

From the above results, it was confirmed that all 7-aminoquinolinonederivatives of the present invention exhibited 50% inhibitoryconcentration of approximately 1 μmol/L or less, and inhibited theoxidative reaction by peroxynitrite.

Example 4

This test was performed so as to evaluate the pharmacological effect ofthe 7-aminoquinolinone derivatives of the present invention in an airwayhyper-responsiveness model induced by inhalation of ozone in guineapigs. The test procedure will now be described.

(Preparation of Airway Hyper-Responsiveness Model)

Guinea pigs were fasted for 18 hours or more. The animals wereadministered the test substance (30 mg/kg) and theophylline (100 mg/kg)one hour before ozone inhalation. For the non-stimulation group and thevehicle control group, vehicle (5 mL/kg) was administered similarly.

The animals were put into an acryl-made chamber (29×19×25 cm), subjectedto induction of ozone generated by an ozonizer (EUV3-XU; EBARA JITSUGYOCO, LTD.) and exposed for 2 hours. The ozone concentration in thechamber was approximately 3 ppm. It was confirmed every 30 minutes thatthis concentration was maintained during exposure by an ozone monitor(EG-5000; EBARA JITSUGYO CO, LTD.) (measured value: 2.53 to 3.40 ppm).For the non-stimulation group, the animals were exposed to a mixed gas(oxygen: 95%, carbonic acid gas: 5%) similarly. The ozone concentrationat that time was also confirmed similarly (acceptable concentration:0.01 ppm or less, measured value: 0.00 to 0.01 ppm).

(Measurement of Airway Hyper-Responsiveness for Methacholine)

The measurement of airway hyper-responsiveness was performed 5 hoursafter the end of ozone exposure. The measurement of lung resistance(RLung) was performed according to the method of R. E. Giles et al. inthe same manner as in Example 2. That is, the animals were anesthetizedwith Nembutal (Trade name: 50 mg/kg, i.p., sodium pentobarbital) andsubjected to cannulation into esophagus and trachea. The esophagus andtrachea cannulas were connected to a respirator (ventilation volume: 6mL/kg, ventilation frequency: 60 times/min, SN-480-7) and the RLungafter inhalation of methacholine (100 μg/mL, for 1.5 minutes) wasmeasured by the respiratory function analyzer (PULMOS-II; M.I.P.S)through a flow sensor (connected to Validyle DF45F (for flow rate) andDP45P (for pressure)). The inhalation of methacholine was performed withan ultrasonic nebuliser (NE-U17; Omron Matsuzaka) connected to therespirator under artificial respiration.

Used RLung represents 10 breaths having a stable value in a range from 1to 30 breaths after initiation of each measurement for both beforeinhalation and during methacholine inhalation. The average of the RLungwas calculated. The extreme values in RLung that occurred when animalmoved during the measurement were excluded from the calculations.

The percentage of increase of RLung was calculated by the followingequation.

Increase in lung resistance (%)=([RLung after inhalation ofmethacholine]−[RLung before administration])/[RLung beforeadministration]×100

TABLE 20 Increase in lung resistance (%) Compound Increase (%) CompoundIncrease (%) 32 32 359 31 53 29 396 22 55 26 401 25 56 30 459 26 58 27514 31 87 29 519 26 147 29 546 27 173 30 549 28 181 25 551 22 204 37 55328 236 28 556 25 276 30 581 30 303 27 Theophylline 26 309 34 Controlgroup 60 330 22 Non-stimulation 0 group

From the above results, it was confirmed that the 7-aminoquinolinonederivative of the present invention (dose: 30 mg/kg) showed, in spite oflow dose, the effect which is almost equal to or greater than that of anexisting drug, theophylline (dose: 100 mg/kg). Therefore, it is clearthat the 7-aminoquinolinone derivatives of the present invention inhibitan increase in lung resistance induced by ozone inhalation.

Example 5 5% Powders

Compound of the present invention  50 mg Lactose  950 mg 1000 mg

Preparation example of powders of compounds 32 and 53 will be shown. Thecompound of the present invention was pulverized in a mortar andthoroughly mixed with lactose. The mixture was pulverized with a pestleto obtain 5% powders of compounds 32 and 53.

Example 6 10% Powders

Compound of the present invention  100 mg Lactose  900 mg 1000 mg

Preparation examples of powders of compounds 236 and 276 will be shown.In the same manner as in Example 5, 10% powders of compounds 236 and 276were prepared.

Example 7 10% Granules

Compound of the present invention  300 mg Lactose 2000 mg Starch  670 mgGelatin  30 mg 3000 mg

Preparation example of granules of compounds 303, 309, 330 and 359 willbe shown. The compound of the present invention was mixed with theequivalent amount of starch and pulverized in a mortar. The mixture wasfurther mixed with lactose and the remaining portion of starch.Separately, 30 mg of gelatin was mixed with 1 ml of purified water,solubilized by heating, cooled and then mixed with 1 ml of ethanol whilestirring to prepare a gelatin solution. Thereafter, the mixture preparedabove was mixed with the gelatin solution and the resulting mixture waskneaded, granulated, dried and then sized to obtain granules ofcompounds 303, 309, 330 and 359.

Example 8 5 mg Tablets

Compound of the present invention 5 mg Lactose 62 mg Starch 30 mg Talc 2mg Magnesium stearate 1 mg 100 mg/tablet

Preparation example of tablets of compounds 514 and 519 will be shown. A20 times larger portion of the above composition was used to preparetablets each of which containing 5 mg of the active ingredient. That is,100 mg of the compound of the present invention in a crystal form waspulverized in a mortar and mixed with lactose and starch. The thusprepared formulation was mixed with 10% starch paste, and the mixturewas kneaded and then subjected to granulation. After drying, theresulting granules were mixed with talc and magnesium stearate and thencompressed in the usual manner. With the above procedure, tablets ofcompound 514 and 519 were prepared.

Example 9 10 mg Capsules

Compound of the present invention  300 mg Lactose 2000 mg Starch  670 mgGelatin  30 mg 3000 mg

Preparation example of capsules of compounds 546, 549, 551 and 553 willbe shown. Granules were prepared in the same manner as in Example 7 andpacked in capsules in 100 mg portions. With the above procedure,capsules of compound 546, 549, 551 and 553 were prepared.

INDUSTRIAL APPLICABILITY

A drug comprising, as an active ingredient, at least one of a7-aminoquinolinone derivative of the present invention and itsphysiologically acceptable salt has high safety and exhibitseffectiveness against chronic obstructive pulmonary disease andtherefore the drug can be utilized medically as a therapeutic agent forchronic obstructive pulmonary disease.

1. A therapeutic agent for chronic obstructive pulmonary diseasecomprising, as an active ingredient, at least one of a7-aminoquinolinone derivative represented by the general formula (I):

wherein R₁ represents a hydrogen atom or an alkyl group; R₂ and R₃ eachrepresents a group selected from a hydrogen atom, an acyl group, analkyl group and an alkenyl group; and R₄ and R₅ each represents a groupselected from a hydrogen atom, an acyl group, an alkyl group, an alkenylgroup and an aralkyl group, and its physiologically acceptable salt. 2.The therapeutic agent for chronic obstructive pulmonary diseaseaccording to claim 1, wherein R₁ represents a hydrogen atom, or a linearor branched alkyl group having 1 to 10 carbon atoms.
 3. The therapeuticagent for chronic obstructive pulmonary disease according to claim 1,wherein R₂ and R₃ each represents a hydrogen atom, an acyl group, alinear or branched alkyl group having 1 to 10 carbon atoms, or a linearor branched alkenyl group having 2 to 10 carbon atoms.
 4. Thetherapeutic agent for chronic obstructive pulmonary disease according toclaim 1, wherein R₄ and R₅ each represents a hydrogen atom, an acylgroup, a linear or branched alkyl group having 1 to 10 carbon atoms, alinear or branched alkenyl group having 2 to 10 carbon atoms, or anaralkyl group.
 5. The therapeutic agent for chronic obstructivepulmonary disease according to claim 1, wherein R₁ represents a hydrogenatom, or a linear or branched alkyl group having 1 to 10 carbon atoms;R₂ and R₃ each represents a hydrogen atom, an acyl group, a linear orbranched alkyl group having 1 to 10 carbon atoms, or a linear orbranched alkenyl group having 2 to 10 carbon atoms; and R₄ and R₅ eachrepresents a hydrogen atom, an acyl group, a linear or branched alkylgroup having 1 to 10 carbon atoms, a linear or branched alkenyl grouphaving 2 to 10 carbon atoms, or an aralkyl group.
 6. The therapeuticagent for chronic obstructive pulmonary disease according to claim 5,wherein R₂ represents a hydrogen atom, and R₃ represents a linear orbranched alkyl group having 1 to 10 carbon atoms, or linear or branchedalkenyl group having 2 to 10 carbon atoms.
 7. The therapeutic agent forchronic obstructive pulmonary disease according to claim 5, wherein R₂represents a linear or branched alkyl group having 1 to 10 carbon atoms,or a linear or branched alkenyl group having 2 to 10 carbon atoms, andR₃ represents a hydrogen atom.
 8. The therapeutic agent for chronicobstructive pulmonary disease according to claim 6, wherein R₄represents a hydrogen atom, and R₅ represents a hydrogen atom, an acylgroup, a linear or branched alkyl group having 1 to 10 carbon atoms, alinear or branched alkenyl group having 2 to 10 carbon atoms, or anaralkyl group.
 9. The therapeutic agent for chronic obstructivepulmonary disease according to claim 8, wherein R₅ represents an acylgroup.
 10. The therapeutic agent for chronic obstructive pulmonarydisease according to claim 9, wherein R₅ represents an acyl groupcomprising a cinnamoyl group which may have a substituent.
 11. Thetherapeutic agent for chronic obstructive pulmonary disease according toclaim 10, wherein R₅ represents a 4-hydroxy-3-methoxycinnamoyl group ora 3,5-dimethoxy-4-hydroxycinnamoyl group.
 12. The therapeutic agent forchronic obstructive pulmonary disease according to claim 1, wherein thechronic obstructive pulmonary disease is chronic bronchitis.
 13. Thetherapeutic agent for chronic obstructive pulmonary disease according toclaim 1, wherein the chronic obstructive pulmonary disease is pulmonaryemphysema.
 14. Use of the therapeutic agent for chronic obstructivepulmonary disease according to claim 1 for treating chronic obstructivepulmonary disease.
 15. A method for treating chronic obstructivepulmonary disease, which comprises using the therapeutic agent forchronic obstructive pulmonary disease according to claim
 1. 16. Use ofat least one of a 7-aminoquinolinone derivative represented by thegeneral formula (I);

wherein R₁ represents a hydrogen atom or an alkyl group; R₂ and R₃ eachrepresents a group selected from a hydrogen atom, an acyl group, analkyl group and an alkenyl group; and R₄ and R₅ each represents a groupselected from a hydrogen atom, an acyl group, an alkyl group, an alkenylgroup and an aralkyl group, and its physiologically acceptable salt, forpreparing a therapeutic agent for chronic obstructive pulmonary disease.17. The therapeutic agent for chronic obstructive pulmonary diseaseaccording to claim 7, wherein R₄ represents a hydrogen atom, and R₅represents a hydrogen atom, an acyl group, a linear or branched alkylgroup having 1 to 10 carbon atoms, a linear or branched alkenyl grouphaving 2 to 10 carbon atoms, or an aralkyl group.
 18. The therapeuticagent for chronic obstructive pulmonary disease according to claim 17,wherein R₅ represents an acyl group.
 19. The therapeutic agent forchronic obstructive pulmonary disease according to claim 18, wherein R₅represents an acyl group comprising a cinnamoyl group which may have asubstituent.
 20. The therapeutic agent for chronic obstructive pulmonarydisease according to claim 19, wherein R₅ represents a4-hydroxy-3-methoxycinnamoyl group or a 3,5-dimethoxy-4-hydroxycinnamoylgroup.